HHV-6 and -7 are two closely related 2-herpesviruses that infect over 90% of the population. These opportunistic viruses do not cause serious illness in healthy people, but in immunocompromised individuals, these viruses can reactivate and cause life-threatening encephalitis and CMV disease. Like all other herpesviruses, HHV-6 and -7 persist or remain latent in their hosts throughout life. In so doing, herpesviruses have evolved numerous strategies to escape detection by the immune system. Notably, all of the herpesviruses thus far examined interfere with viral antigen presentation to cytotoxic T lymphocytes (CTLs) by removing class I MHC molecules from the infected cell surface. Clearly, since the herpesviruses have evolved such an extensive array of mechanisms to remove class I MHC molecules from the cell surface, this strategy serves them well. However, when Natural Killer (NK) cells detect an absence of class I MHC molecules on the surface of a cell (i.e., "missing self"), they become activated to kill that cell. The focus of this application is to discover how HHV-6 and -7 evade the NK and CTL cell responses to viral infection. Several strategies will be employed to identify novel viral immunoevasins that allow HHV-6/-7 infected cells to escape detection: 1) we will explore the function of open reading frames within HHV-6 and -7 that have obvious homology to immune molecules. 2) We will screen HHV-6 and -7- infected antigen-presenting cells for the surface downregulation of candidate cellular membrane proteins involved in the initiation of a cytolytic response against an infected cell. The long term goal of this project is to understand the mechanisms by which HHV-6 and -7 evade detection by the immune system. Revelation of the mechanisms by which these opportunistic viruses evade the immune system will not only contribute to the understanding of these viruses and their pathogenesis, but also to the understanding of basic underlying principles of cell biology. Ultimately, the knowledge gained from understanding how these molecules function to subvert the immune response may lead to the identification of potential therapeutic targets for the treatment of these opportunistic infections, as well as for the treatment of autoimmune disorders.